There are more than 3 million people currently living with diabetes in the United Kingdom, according to the International Diabetes Federation, and it is estimated that nearly 200 000 individuals in this country currently experience vision loss as a result of diabetic macular edema (DME). As the burdens of diabetes and diabetic eye disease grow throughout the developed world, new approaches to treatment will become increasingly important. Therapeutic options that can reduce the frequency of treatment will be particularly vital, particularly in countries with socialized health care systems such as the United Kingdom.
Ophthalmologists in this country were therefore heartened by the news that the UK Medicines and Healthcare Products Regulatory Agency (MHRA) granted marketing authorization in May for an extended-release fluocinolone acetonide (FA) intravitreal implant (Iluvien, Alimera Sciences) for the treatment of vision impairment associated with chronic DME considered insufficiently responsive to other available therapies.
The Iluvien FA implant is inserted into the posterior chamber through a self-sealing wound in an outpatient procedure using a 25-gauge needle applicator. The nonbiodegradable insert contains 190 μg FA, which is released in a sustained manner, providing a therapeutic effect for up to 36 months.
The UK authorization is the second national approval of the FA implant in the European Union, following approval by Austria in April. Other national marketing authorizations are expected in the EU in coming months.
Despite the marketing authorization, however, physicians in this country do not yet have the FA implant in their hands. We are waiting for the UK National Institute for Health and Clinical Excellence (NICE) to provide guidance to the National Health Service (NHS) on reimbursement for the implant. The NICE is an independent health authority that attempts to provide evidence-based guidelines to the NHS regarding which medicines, procedures, and devices represent the best quality care and the best monetary value for the government.
UK physicians, working in a socialized health care system, are used to bureaucratic delays, although we still find them frustrating. Having used the FA implant as one of the investigators in the FAME study, I understand the potential for this device to potentially reduce the burden of repeated treatments for patients with DME and other posterior segment pathologies.
The FAME study consisted of 2 almost identical 36-month phase 3 clinical trials including 956 patients at sites across Europe, the United States, Canada, and India. These studies assessed the safety and efficacy of 2 doses of the FA implant in patients with DME.1
In both clinical trials, a statistically significant treatment benefit was seen in the primary endpoint of the study, the percentage of improvement from baseline of 15 or more letters in best corrected visual acuity (BCVA) at 24 months. Almost 30% of treated patients gained 15 or more letters in each trial, and a statistically significant difference from the control arm was maintained in each trial as late as month 33.
Of particular interest were the results seen in a subgroup of 536 patients with chronic DME—those diagnosed with DME for 3 years or more before entry in the study. In the chronic DME patients who received the FA implant, 31.8% (P = .01) in Trial A and 36.4% (P = .004) in Trial B experienced BCVA improvement of 15 or more letters from baseline at 36 months. Among patients in this subgroup who received the control treatment, 13.6% in Trial A and 13.2% in Trial B experienced that level of BCVA improvement at 36 months.
Similar to the full patient population, approximately 75% of the patients treated with the FA implant in this chronic DME subgroup received only one insert over the course of the 36-month study.
Although I was an investigator in the FAME Study, I was masked to the results in individual patients during the study, so it is difficult for me to present individual case examples illustrating the safety and efficacy of the FA implant. Our perception was that the patients did well.
Certainly the overall results of the study point to potential advantages of this type of extended-release therapy over the options we currently have for treatment of DME in the UK. In the publicly funded NHS, we can perform laser treatment or give intravitreal steroid injections to treat DME. Most NHS hospitals are currently not allowed to use intravitreal anti-VEGF agents for this indication. There are a few exceptions, but often permission is granted only for a small number of patients or on a case-by-case basis following review by health care commissioners. Our mainstay of treatment for the majority of DME patients to date therefore has been laser, and a small percentage are treated with intravitreal triamcinolone. The patients we enrolled for the FAME trial included those for whom we thought laser treatment might not be the best option.
The results of the study, showing that patients with chronic DME of more than 3 years had significantly better results, were surprising and interesting to us as clinicians. One would have expected these patients to be less responsive to other forms of treatment such as laser. The implant is therefore potentially very useful for this group of patients.
Another potential advantage is its duration of action. Our experience in age-related macular degeneration, for which we give monthly injections of anti-VEGF agents, is that the repeated injections over the course of months and years are onerous for both patients and doctors. It would be very attractive to have a treatment for DME that could potentially last 3 years.
We found the injector instrument very easy to use, compared to some other injectors with which we have experience. The device is technically well adapted, and the drug is easy to administer. It is advantageous to have a long-lasting implant that can be inserted in an in-office procedure.
Until the NICE provides guidance on the FA implant, its clinical availability for treatment of DME in this country is unlikely to change. The NICE guidances are based on complex cost-effectiveness calculations, including sophisticated mathematical modeling. Often with new treatments there is not a lot of data with which to develop and assess these models, and it is a challenge to calculate the effect of visual acuity measurements on quality of life. In addition, to ensure transparency and fair play, the NICE decisions can be challenged and subsequently revised.
All of this takes time. It would be wonderful if a tool such as the FA implant were available now for treating DME, but UK physicians are used to these decisions taking many months. Unfortunately, without certification from the NICE it is difficult for us to obtain funding for these treatments on the NHS.
It is expected that the NICE ruling will give guidance on indications for the implant, perhaps a range of visual acuity or a certain degree of chronicity, such as DME of more than 3 years duration, based on the clinical trial results. We will not know until we see the ruling. The cost of the drug will also be a factor in the ruling.
Once it becomes available, the FA implant is certain to be an important tool for us in the treatment of DME. Its duration of action will be a valuable asset, as retina physicians in every country are struggling to meet the demands of administering frequent intravitreal injections in a safe manner. A 3-year period of efficacy will compare favorably with other treatments that require monthly or even bimonthly or quarterly injections.
Andrew Lotery, MD, FRCOphth, is a Professor of Ophthalmology and Director of the Clinical Neurosciences Research Group, Clinical and Experimental Sciences, on the Faculty of Medicine at the University of Southampton, in Southampton, UK. Dr. Lotery states that he is a paid consultant for Alimera Sciences. He can be reached at +44 (0) 23 8079 5049; email: A.J.Lotery@soton.ac.uk.
- Antoszyk A, for the FAME Study Group. Efficacy and safety of Iluvien (fluocinolone acetonide [FAC] intravitreal insert) for the treatment of diabetic macular edema. Paper presented at: Association for Research in Vision and Ophthalmology Annual Meeting; May 3, 2011; Fort Lauderdale, FL. Abstract #6645.